Annealed composition for pharmaceutically acceptable drug

ABSTRACT

A dosage form is disclosed comprising a coat that surrounds a drug. The coat comprises a subcoat and an overcoat thermally annealed to provide a single unit coat around the drug.

CROSS-REFERENCE TO RELATED APPLICATON

This application is a continuation-in-part of U.S. Appln. Ser. No.07/350,482 filed on May 11, 1989, now U.S. Pat. No. 5,006,346 issuedApr. 9, 1991 which application Ser. No. 07/350,482 is a division of U.S.Pat. Appln. Ser. No. 07/187,621, filed Apr. 28, 1988 now U.S. Pat. No.4,931,285 issued Jun. 5, 1990, which applications are incorporatedherein by reference and benefit is claimed of its filing date. Theseapplications are assigned to the ALZA Corporation of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to both a novel and useful pharmaceuticalcoating composition. More particularly, the invention relates to apharmaceutically acceptable coating composition on dosage forms such asdelivery devices comprising a core comprising a therapeutically activedrug; osmotic delivery systems; tablets; capsules; powders; granules;and beads.

BACKGROUND OF THE INVENTION

In Remington's Pharmaceutical Sciences, 14th Ed., p 1681, published in1970, it is reported that pill coating has been a pharmaceuticaltechnique for well over ten centuries. For example, Rhazes (850-932A.D.) used a mucilage for coating pills in the ninth century andAvicenna (980-1037 A.D.) is credited with the introduction of silver andgold pill coatings into medicine. The coating of pills with finelypowdered talcum, called pearl coating, was popular at one time. Gelatincoating of pills was introduced by Garot in 1838. The first sugar-coatedpills in the United States were imported from France in about 1842. Thefirst sugar-coated pill manufactured in the United States was in 1856 byWarner, a Philadelphia pharmacist. The coating of pills with tolu wasdone in about 1860, and twenty-four years later Unna introduced entericcoated pills.

Various pharmaceutically indicated articles of manufacture have beencoated by the drug dispensing art. For example, tablets were coated toprovide a more attractive dosage form, to protect its drug content frommoisture and to enhance its taste. Then too, tablets were provided witha coat for releasing a drug by enteric dissolution in the intestine of awarm-blooded animal. Recently osmotic dosage forms were coated with asemipermeable rate controlling wall for delivering a drug at a knownrate per unit time.

While the above mentioned dosage forms are useful in the management ofhealth and disease, serious disadvantages are associated with them. Thatis, usually organic solvents are used for applying the coating to thedrug and drawbacks accompany the use of organic solvents. For example,organic solvents generally are toxic and they must be substantiallyremoved, usually by vacuum or by air ciruclation, from the dosage formto avoid hazard to health the dosage form's recipient. Another drawbackis that most organic solvents are flammable thereby possibly providingthe danger of fire to the manufacturer. Also, organic solvents presentan environmental problem and they require complicated recovery systemsto avoid contaminating the environment, which systems are expensive tooperate. It will be appreciated by those skilled in the drug dispensingart that if a coating is provided that is substantially-free of organicsolvents for coating drugs, drug granules, drug powders, drug deliverydevices, and the like, such a coating would have an immediate positivevalue and, concomitantly, represent an advancement in the drug coatingart. Likewise, it will be appreciated by those versed in the dispensingart that if a delivery device is made available comprising a coatingapplied from a non-organic solvent, and which delivery device possessesthe thermodynamic ability to deliver a beneficial drug at a controlledrate, such a delivery device would have a practical application in thefields of human and veterinary medicine.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a novel and useful coatingcomposition for dosage forms and which coating overcomes thedisadvantages associated with the prior art.

Another object of this invention is to provide a new coating compositioncomprising pharmaceutically acceptable ingredients, and which coatingcomposition is innocuous and useful for manufacturing dosage forms.

Another object of this invention is to provide a non-toxic coatingcomposition free of organic solvents and which coating composition isuseful for making dosage forms by standard manufacturing techniques.

Another object of the invention is to provide an aqueous coatingcomposition which is relatively uncomplicated, capable of applicationwithout difficulty, and is applied at a relatively low cost.

Another object of the invention is to provide an aqueous polymericcoating that exhibits stability and resistance to sedimentation.

Another object of the invention is to provide an aqueous coatingcomposition useful for manufacturing a drug delivery device possessingdrug release rate controlling properties.

Another object of this invention is to provide a drug delivery devicethat can be manufactured by standard manufacturing techniques intovarious sizes, shapes and forms that comprise an improvement in thedispensing art, which comprises a non-toxic, aqueous coated wall thatsurrounds a drug.

Another object of this invention is to provide an aqueous-solventcoating composition that is non-flammable and is not an environmentalhazard during formulation and not a hazard when applied to a drug core.

Another object of the invention is to provide a novel coatingcomposition comprising a water carrier useful for coating a drug.

Other objects, features and advantages of this invention will be moreapparent to those versed in the dispensing art from the followingdetailed specification taken in conjunction with the drawings and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is an opened view depicting a powdered drug coated with thecoating composition provided by this invention;

FIG. 2 is an opened view illustrating granules of a beneficial drugcoated with a coating composition provided by this invention;

FIG. 3 is a view of an osmotic device designed and shaped for orallyadministering a beneficial drug to the gastrointestinal tract;

FIG. 4 is an opened view of the osmotic device of FIG. 3 depicting thewall of the osmotic device comprising the wall-forming coatingcomposition of this invention;

FIG. 5 is a view of another embodiment of an osmotic device provided bythis invention, which osmotic device is adapted and sized for oraladmittance into the gastrointestinal tract of a host;

FIG. 6 is an opened view of the osmotic system of FIG. 5 forillustrating a wall formed from the coating composition provided by thisinvention;

FIG. 7 is a graph that depicts the drug delivery rate per unit time froma device comprising a wall coated by the process of the invention; and,

FIG. 8 is a graph that depicts the cumulative amount of drug releasedper unit time by the delivery device of FIG. 7.

In the drawings and in the specification like parts in related figuresare identified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawing figures in detail, which figures are examplesof a dosage form comprising a coating composition provided by thisinvention and which examples are not to be considered as limiting theinvention, one example of a dosage form is illustrated in FIG. 1. InFIG. 1, a dosage form 10 is seen in opened section. Dosage form 10comprises a powdered drug 11, generally exhibiting a powder size thatpasses through a sieve having an opening of from 0.074 mm to 0.250 mm,surrounded by coating composition 12. Coating composition 12 comprises asubcoat and an overcoat. The subcoat comprises a finely divided membraneforming polymer dispersed in an oil-in-water emulsion, wherein the oil,generally present as an oily plasticizer, lowers the glass transitiontemperature of the membrane forming polymer. The overcoat comprises awater soluble composition wherein the glass transition temperature ofthe overcoat is higher than that of the subcoat. The subcoat and theovercoat are annealed, with the subcoat forming an insoluble membranethat surrounds powdered drug 11. The annealed overcoat forms a membranethat dissolves in an aqueous environment of use, leaving a continuous,insoluble membrane coating 12.

In FIG. 2, another embodiment of dosage form 10 is seen in opened view.In FIG. 2 dosage form 10 comprises granules of drug 13. The druggranules generally exhibit a granule size that passes through a sievehaving an opening from greater than 0.250 mm to 9.50 mm. Drug granules13 are surrounded by aqueous-applied coating composition 14. Coatingcomposition 14 is applied in two steps, first a subcoat followed by anovercoat. The two coats are annealed, which annealing process coalescesthe polymer in the subcoat thereby providing a continuous membrane orfilm. The overcoat protects the subcoat during the annealing process andthe overcoat additionally prevents the subcoat of one dosage form fromfusing with the subcoat of a neighboring dosage form.

In FIG. 3, another embodiment of dosage form 10 is illustratedmanufactured as an osmotic drug delivery device. In FIG. 3 osmoticdosage form 10 comprises a body 15 comprising a wall 16 that surroundsand forms an internal compartment, not seen in FIG. 3. Osmotic dosageform 10 comprises at least one passageway 17 for connecting the interiorof osmotic dosage form 10 with the exterior of osmotic dosage form 10when in a biological environment of use.

In FIG. 4 osmotic dosage form 10 of FIG. 3 is seen in opened view. InFIG. 4 osmotic dosage form 10 comprises body member 15, aqueous coatedwall 16 and exit passageway 17. Wall 16 surrounds and forms an internalcompartment 18. Internal compartment 18 comprises a dispensable drug 19,represented by dots, and an optional osmagent, represented by dashes.Wall 16 is permeable to the passage of an exterior fluid present in theenvironment of use, and wall 16 is substantially impermeable to thepassage of drug 19 and osmagent 20.

In FIG. 5 another embodiment of dosage form 10 is illustrated and madeas an osmotic drug delivery device. In FIG. 5 osmotic dosage form 10comprises a body member 21 comprising a wall 22 that surrounds and formsan internal compartment, not seen in FIG. 5. Dosage form 10 comprises atleast one passageway 23, formed during the manufacture of dosage form 10or, optionally, formed when dosage form 10 is in a fluid environment ofuse. Passageway 23 connects the interior of dosage form 10 with itsexterior for delivering a drug to an environment of use.

In FIG. 6 dosage form 10 of FIG. 5 is seen in opened view. In FIG. 6dosage form 10 comprises body member 21, aqueous coated annealed wall 22and exit passageway 23. Wall 22 surrounds, forms and defines an internalcompartment 24. Internal compartment 24 comprises a first compositionidentified by dots 25, and a second composition 26 identified byvertical lines. First composition 25 comprises a beneficial drug andsecond composition 26 comprises an expandable hydrogel. Firstcomposition 25 and second composition 26 are in laminar arrangement andthey cooperate with wall 22 for the effective delivery of a drug throughexit passageway 23 to an environment of use.

FIG. 7 and FIG. 8 exemplify the release of an active agent from adelivery system made according to this invention. The release rate perunit time and the cumulative amount release of the drug potassiumchloride are depicted, respectively, for a delivery system madeaccording to this invention.

While FIGS. 1 through 8 illustrate different embodiments of dosage formsthat can be coated with the coating composition of this invention, it isto be understood that the coating composition can be applied to a widevariety of dosage forms, which dosage forms comprise various shapes,sizes and forms. The coating composition can be applied to devices notlimited to but including uses for buccal, implant, artificial gland,cervical, intrauterine, nose, and the like. In these forms the devicecoated with the coat of this invention can be adapted for administeringa beneficial medicine to animals, warmblooded mammals, humans, farm andzoo animals, avians and reptiles.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention a drug or the like isfirst coated with a subcoat followed by an overcoat. The subcoatcomprises a membrane forming polymer, a plasticizer, an emulsifier, anoptional hydrophilic enhancer, and an aqueous carrier. The overcoatcomprises a membrane or film forming polymer, an optional plasticizerand an optional carrier. The polymeric material used for forming thesubcoat, which subcoat when the dosage form is in operation in a fluidenvironment of use, comprises the sole coat on the form and is a polymerthat is nontoxic and does not adversely affect a beneficial drug and ananimal host, including humans. In a presently preferred embodiment,polymeric materials useful for providing the subcoat comprise polymericmembers selected from the group consisting of a cellulose ester,cellulose ether, cellulose ester-ether, cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetateand cellulose triacetate. More specific examples of polymeric materialscomprise a member selected from the group consisting of celluloseacetaldehyde methyl carbamate, cellulose acetate succinate, celluloseacetate dimethylaminoacetate, cellulose acetate ethylcarbamate,cellulose acetate dipalmate, cellulose acetate dioctanoate, celluloseacetate dicaprylate, cellulose acetate pentylate, cellulose acetatevalerate, cellulose acetate succinate, cellulose acetate propionate,cellulose acetate p-toluene sulfonate, cellulose acetate butyrate,cellulose propionate butyrate, and the like. Generally the polymer usedfor forming the composition will have a particle size of less than about2 to 15 microns and more, preferably less than about 2 to 10 microns.The amount of polymer on a weight basis of the coating in a final, drycoated dosage form generally is about 15 to 95%.

The subcoating additionally comprises a non-toxic plasticizer or blendsof plasticizers. The plasticizers presently preferred are highboilingsoftening agents, which are often liquids, pastes, or waxes at roomtemperature, that are added to the subcoat composition to facilitateprocessing, and to increase flexibility and toughness. The plasticizersgenerally comprise, in a presently preferred embodiment, a memberselected from the group consisting of monoglycerides, diglycerides,triglycerides, alkyl phthalyl alkyl glycolates, trialkyl esters of acylcitric acid, dialkyl adipates, dialkyl phthalates, dialkyl sebacates,fatty acid ester derivatives, akyl-aryl phosphates, fatty acid esters ofpolysaccharides, triethyl citrate, acetyltriethyl citrate, diethylphthalate, diethyl tartrate, dibutyl phthalate, dibutyl sebacate,dibutyl tartrate, dibutyl maleate, dibutyl succinate, diethyl succinate,propylene glycol, glycerin, monoacetin, diacetin, triacetin,polyethylene glycol, di(methoxyethyl) phthalate, methyl and ethylphthalate ethyl glycolate, butyl phthalyl butyl glycolate, benzylphthalate, ethylene glycol diacetate, methylglycol phthalate, ethyleneglycol monoacetate, trimethyl phosphate, triethyl phosphate, dioctyladipate, dioctyl phthalate, dibutyloxyethyl phthalate, epoxidizednatural glyceride of unsaturated fatty acids, soybean oil epoxide,di-n-hexyl azelate, dimethyl phthalate, diphenyl phthalate butylstearate, diethyl oxalate, di-isodecyl adipate, dicyclohexyl phthalate,di(2-ethylhexyl) adipate, cresyldiphenyl phosphate, tributyl citrate,acetyl tributyl citrate, trimethyl citrate, acetyltri-n-hexyl citrate,n-butyryltri-n-hexyl citrate, tricyclohexyl citrate,acetyltri-n-(hexyl/octyl/decyl) citrate, acetyltri-n-(octyl/decyl)citrate, acetyltri-n-(decyl/dodecyl)citrate, tristearyl citrate, stearylcitrate-mono, methylglycol stearate, butyl phthalyl butyl glycolate,tri(n-octyl/n-decyl) trimellitate, triisodecyl trimellitate, tri-n-hexyltrimellitate, di(2-ethylhexyl) isophthalate, butyl ricinoleate,polymeric plasticizer acetylated, citric acid esters, natural oils andderivatives of natural oils, fish oils, lard oils, vegetable oils,babassu oil, castor oil, coconut oil, cottonseed oil, corn oil, linseedoil olive oil, palm oil, peanut oil, safflower oil, seasme oil, soybeanoil, tall oil, acetyl tri-2-ethylhexyl citrate, linoleic acid, oleicacid, butyl sterate, benzyl benzoate, polysiloxanes, silcone oils,mineral oils, hydrogenated oils, methyl ester of rosin, stearic acid,cetyl alcohol, acetylated glycerides, glycerol esters, polyethyleneglycol, and the like. The amount of plasticizing agent in a finalsubcoat on a drug delivery dosage form is about 2% to 75%.

The subcoat comprises also an emulsifying agent or blends of emulsifyingagents. The emulsifying agents generally are surface active agentscomprising anionic, polar, nonpolar, amphoteric, zwitterionic andcationic active emulsifying agents. The amount of emulsifying agents inan aqueous coating composition usually is about 0.1% to 20%, and morepreferably about 0.01% to 4%, by weight, of water in the aqueous phase.Representatives of general classes of emulsifying agents comprise amember selected from the group consisting essentially of alkanolmides,alkyl sulfonates, amines and amides sulfonated, betaine emulsifiers,diphenyl sulfonates, ethoxylated alcohols, ethoxylated alkyl phenols,ethoxylated amines, ethoxylated amides, ethoxylated fatty acids andoils, fatty esters, florocarbons, glycerl esters, glycol esters,heterocyclic emulsifiers, isethionates, lanolin based emulsifiers,lecithin based emulsifiers, phospholipids, lignin emulsifiers,monoglycerides, olefin sulfonates, phosphate emulsifiers, phosphateesters emulsifiers, polyamino carboxylic emulsifiers, proteinemulsifiers, quaternary emulsifiers, sarcosine emulsifiers, siliconeemulsifiers, siloxane emulsifiers, sorbitan emulsifiers, sulfo succinateemulsifiers, sucrose esters, ethoxylated alcohol sulfates, ethoxylatedalcohol sulfates, sulfates and sulfonates of ethoxylated alkyl phenols,sulfates of fatty acids, sulfates of oils, sulfonates of oils, sulfatesof fatty acids, sulfonates of fatty acids, sulfonates of alkyl aryls,sulfonates of naphtholenes, sulfonates of dodecyl and tridecylbenzenes,sulfonates of petroleum, tridecyl and dodecyl benezene sulfonic acids,taurates, tertiary amine oxides, and thio and mercapto emulsifiers.Representatives of nonionic emulsifying agents include polyoxyethylenesorbitan tristearate, polyoxyethylene sorbitan mono-oleate,polyoxyethylene sorbitan monopalmitate, sorbitan monopalmitate,polyoxyethylene sorbitan tri-oleate, polyoxyethylene sorbitanmonostearate, polyoxyethylene alkyl phenol, polyoxyethylene sorbitanmonolaurate, polyoxyethylene oxypropylene stearate, glycerolmonostearate, propylene glycol fatty acid ester, and the like.Representatives of anionic emulsifying agents include triethanolamineoleate, sodium oleate, calcium stearoxyl-2-lactylate, calciumdodecylbenzene sulfonate, ammonium lauryl sulfate, sodium alkyl sulfate,triethanolamine lauryl sulfate, sodium dodecylsolfate, and the like.Exemplary cationic emulsifiers include high molecular weight fatty amineblends, polyoxyethylene fatty amines, polyoxyethylene tallow amines,N-cetyl-N-ethyl morpholinium ethyl sulfate, and the like. Theemulsifiers are known in McCutcheon's Detergents and Emulsifiers, NorthAmerican Edition (1979) and International Edition (1979), in theEncyclopedia of Chemical Technology, by Kirk-Othmer, 3rd Ed. Vol. 8, pp900-30, (1984), and in the Cosmetic, Toiletry, and Fragrance AssociationCosmetic Ingredient Dictionary 3rd Ed., (1982) and 3rd Ed., Supplement(1985).

The subcoat comprises an optional hydrophilic enhancer or blends ofhydrophilic enhancers that aid in transporting fluid from theenvironment of use into a dosage form. The hydrophilic enhancers in oneembodiment are polyhydric alcohols and derivatives thereof, such aspolyalkylene glycols of the formula H-(O-alkylene)_(n) OH, wherein thebivalent alkylene radical is a straight or branched chain of from 1 to10 carbons and n is 1 to 500 or higher. Typical glycols comprisepolyethylene glycols 300, 400, 600, 1500, 3350, 4000 and 6000 of theformulae H(OCH₂ CH₂)_(n) OH wherein n is, respectively, 5 to 5.7, 8.2 to9.1, 12.5 to 13.9, 29 to 36, 29.8 to 37, 68 to 84, and 158 to 204. Otherpolyglycols comprise the low molecular weight glycols such aspolypropylene glycol, polybutylene glycol and polyamylene glycol. Otherhydrophilic enhancers include polyvinyl pyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, sorbitol, fructose, mannitol,citric acid, sodium citrate or entirely active materials such as finelydivided cellulose acette trimellitate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, acrylic copolymers, polyvinylacetae phthalate. The amount of hydrophilic enhancer in the aqueousemulsion is 0% to 70%, with water and the concentration of oilingredients in the aqueous coating composition equal to 100%.Hydrophilic enhancers are known in U.S. Pat. No. 4,160,020.

The overcoat annealing composition comprises a water soluble polymersuch as, in a presently preferred manufacture, a member selected fromthe group consisting of hydroxypropyl cellulose, methyl cellulose,methylethyl cellulose, polyvinylpyrrolidone, sodiumcarboxymethylcellulose, hydroxypropylmethyl cellulose, and the like.Other optional annealing agents comprise gums such as pectin, acacia,tragacanth, karaya, locust, bean gum, chondrus and alginic acid. Theovercoat can comprise from 10% to 100% of the final dosage form whenapplied by compression coating. In an optional embodiment the overcoatcan comprise from 0% to 60% of a plasticizer such as glycerin, propyleneglycol glyceryl triacetate, polyethylene glycol, and the like, and waterto 100%. The overcoat comprising the water soluble ingredients can becoated by spraying, dipping, and the like. The overcoat and the subcoatare annealed in a presently preferred embodiment at about 35° C. to 85°C., for 10 to 72 hours in a forced air oven. As an option the annealingprocess can result in causing the plasticizer in the overcoat topartition from the overcoat into the subcoat. The subcoat, overcoat, orboth subcoat and overcoats can, optionally, contain finely dividedinsoluble material. These are useful for reducing tackiness or forenhancing mechanical integrity of the layers. Typical materials for thisapplication wold be microcrystalline cellulose, titanium dioxide orfumed silicon dioxide.

The expression, "exit passageway," as used herein for a drug deliverydevice coated with the composition of this invention, comprises meansand methods suitable for the controlled, metered release of a drug froma drug delivery device or dosage form. The exit means comprise at leastone passageway, orifice, or the like, through the wall of the dosageform. The expression, "at least one passageway," embraces aperature,orifice, bore, pore, porous element, and the like, through which pores adrug can travel, hollow fiber, capillary tube, porous overlay, porousinsert, and the like. The expression also includes a material thaterodes, or is leached from a wall in a fluid environment of use toproduce at least one passageway of controlled releasing dimensions.Representative materials for forming a passageway or two passageways, ora multiplicity of passageways in an environment of use include anerodible, innocuous poly(glycolic) acid, or poly(lactic) acid member inthe wall; a gelatinous filament; a particle of polyvinyl alcohol;leachable materials such as a fluid removable pore formingpolysaccharide, salt, oxide, polyhydric alcohols, and the like. Apassageway or a plurality of passageways of governed dimensions for thecontrolled release of a drug can be formed by leaching a passagewayformer such as sorbitol from a wall. The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, and the like,for assisting in the metered release of a drug from a dosage form. Adosage form can comprise one or more than one passageways in spacedapart relations or, optionally, on more than a single surface of adosage form. Passageways and equipments for forming passageways aredisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864. Representative passageways formed by the governed leaching ofa pore former to produce a pore of precontrolled rate releasing size aredisclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.

The expression, "therapeutically active drug," as used herein, denotes abeneficial medicine neat, or a composition comprising a beneficial drugand other composition forming ingredients. In the specification and theaccompanying claims the terms, "medicine and drugs," are used asequivalents, and the term, "drug," includes any physiologically orpharmacologically active substance that produces a local or a systemiceffect in animals, including warm-blooded mammals, primates and humans.The terms, "physiologically and pharmacologically," are defined inStedman's Medical Dictionary, published by Williams and Wilkins, (1966),Baltimore, MD. The active drug that can be coated with a compositionprovided by this invention includes inorganic and organic drugs, withoutlimitations, comprising drugs that act on the central nervous system,depressants, hypnotics, sedatives, psychic energizers, tranquilizers,anticonvulsants, muscle relaxants, antiParkinsons, analgesics,anti-inflammatories, local anesthetics, muscle contractants,antimicrobials, antimalerials, hormones, contraceptives,sympathomimetics, diuretics, antiparasitics, neoplastics, hypoglycemics,ophthalmics, electrolytes, and cardiovascular drugs. These drugs andtheir daily dosage are known in the art in Pharmaceutical Sciences, byRemington, 16th Ed., (1980), published by Mack Publishing Co., Easton,PA.

The drug can be in various pharmaceutically acceptable forms, such asuncharged molecules, molecular complexes, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulfate, laurylate,palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate,oleate and salicylate. For acidic medicines salts of metals, amines ororganic cations; for example quaternary ammonium can be used.Derivatives of medicines, such as an ester, ether and amides, can beused. Also, a medicine that is water insoluble can be used in a formthat is a water soluble derivative thereof to serve as a solute, and onits release from a dosage form it is converted by enzymes, hydrolyzed bythe body pH, or other metabolic process to the original biologicallyactive form.

Hydrophilic polymers that exhibit an osmotic pressure gradient, imbibefluid and expand, that are useful for manufacturing as coated osmoticdosage forms comprise noncross-linked hydrogels, and lightlycross-linked hydrogels, such as cross-linked by covalent or ionic bonds.The hydrophilic hydrogels usually exhibit a 2 to 50 fold volume increasecomprising acidic carboxy polymer having a molecular weight of 450,000to 4,000,000; poly(hydroxyalkyl methacrylate) having a molecular weightof 30,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weightof 10,000 to 360,000; polyacrylic acid having a molecular weight of80,000 to 200,000; polyethylene oxide polymers having a molecular weightof 100,000 to 5,000,000, sodium salt of carboxymethyl cellulosecross-linked, and the like. Representative polymers that form hydrogelsare known to the prior art in U.S. Pat. No. 3,865,108 issued to Hartop;U.S. Pat. No. 4,002,173 issued to Manning; U.S. Pat. No. 4,207,893issued to Michaels; U.S. Pat. No. 4,327,725 issued to Cortese et al; andin the Handbook of Common Polymers, by Scott and Roff, published byChemical Rubber Co., Cleveland, OH.

The osmagent optionally present in an osmotic dosage form coatedaccording to the mode and the manner of the invention comprise magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate,potassium chloride, sodium sulfate, mannitol, urea, sorbitol, inositol,raffinose, fructose, sucrose, glucose, and the like. The osmagents areknown in U.S. Pat. No. 4,327,725.

The coating composition can be applied to a drug core by standardmanufacturing techniques. For example, one manufacturing procedure isthe air suspension technique. The air suspension procedure consists insuspending and tumbling the drug core to be coated in a current of airand the coating composition until a coat is applied to the drug core.Air suspension procedures are known in U.S. Pat. No. 2,799,241; in J.Am. Pharm. Assoc., Vol. 48, pp 451-59; (1959), and ibid, Vol. 49, pp82-4, (1960). Drug cores can be coated with a coating composition in aWurster® air suspension coater or in an Aeromatic® air suspensioncoater. Other coating procedures such as pan coating can be used forapplying a subcoat or an overcoat. Generally the subcoat will be about 2to 20 mils, usually 3 to 10 mils, thick and the overcoat will be about 1to 12 mils and, more preferably, 1 to 6 mils thick. The polymers used toprovide the subcoat can be milled in a vehicle of either gas or liquidto a fine particle size by using an impact mill, an air jet, amicrofluidizer, an attrition mill, ball mill, cage mill, colloid mill,cone mill, grinding mill, hammer mill, and the like. Another techniquethat can be used to form finely divided polymers is to dissolve thepolymer in an organic solvent, which is emulsified in water with asurfactant and then vacuum-off the solvent. For example, celluloseacetate comprising an acetyl content of 39.8% is dissolved incyclohexanone with sodium lauryl sulfate and the mixture is emulsifiedin water with shear. The cyclohexane then is drawn off under reducedpressure, leaving aqueous dispersion of finely divided celluloseacetate. This dispersed cellulose acetate is then coated according tothe process of this invention. Another example comprises plasticizing apolymer such as ethyl cellulose, melting it and dispersing the melt inwater with high shear and elevated temperature.

DETAILED DESCRIPTION OF THE EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those skilled in the drug delivery art in the light ofthe present disclosure, the drawings and the accompanying claims.

EXAMPLE 1

A drug delivery dosage form adapted, designed and shaped as an osmoticdelivery system is manufactured as follows: first, 64 grams of celluloseacetate having an acetyl content of 39.8% was milled by dispersing it in576 grams of water. This dispersion was passed five times thrugh amicrofluidizer to a particle size of about 5 microns. The slurry wasadded slowly into an emulsion comprising 86.4 g of triacetin, 9.6 g ofpolyoxyethylene-20-sorbitan tristearate, an emulsifier, in 2,464 ml ofdistilled water at 67° C. with vigorous stirring for 15 to 20 minutes.The emulsion was previously prepared by heating the water, emulsifierand the triacetin to 67° C. with stirring for 10 to 15 minutes. Theresulting emulsified coating composition was stirred constantly whilecooled slowly to room temperature over a 2 hour period.

The aqueous subcoat was coated onto 500 mg potassium chloride cores inan Aeromatic® coater by spraying the coating at a fluid pump rate of 6ml/min and at an inlet temperature of 37°-39° C., until about 4.5 milthick coating was applied to each potassium core.

Next, the subcoated cores were overcoated with an overcoat comprising 20g of hydroxypropylcellulose in 780 mil of distilled water using theAeromatic coater. The overcoat was applied at a fluid pumping rate of 2mil/min until a coating about 3 mil thick surrounded the subcoat.

EXAMPLE 2

The above procedure is followed to provide a subcoat comprising 50%cellulose acetate having an acetyl content of 39.8%, 44% triacetin and6% polyoxyethylene sorbitan monolaurate, and an overcoat comprising 93%hydroxypropylcellulose, 6% polyethylene glycol 3350 and 1% titaniumdioxide. The cellulose acetate was milled by passing it six timesthrough an air jet mill until an average particle size of less than 20microns was obtained. The milled powder was sprinkled slowly into anemulsion comprising 86.4 grams triacetin, 9.6 gramspolyoxyethylene-20-tristearate and 3040 ml water, processed with theprocedures detailed in Example 1, except that all mixing was done atambient temperature. The coatings are annealed at 50° C. for 24 hours ina forced air oven.

EXAMPLE 3

A dosage form adapted, designed and shaped as an osmotic drug deliverysystem is manufactured as follows: first, a drug containing compositionas expressed on a percentage basis of the final composition is preparedby passing through a 40 mesh screen 74.40 weight percent (wt %)polyethylene oxide having a molecular weight of 200,000 grams per mole.Then, 20.10 wt % of nifedipine and 5.00 wt %hydroxypropylmethylcellulose having an average molecular weight of11,200 grams per mole is added to the polyethylene oxide and the threeingredients mixed for about 10 minutes in a conventional mixer. Whilethe three ingredients are mixing, denatured, anhydrous ethanol is addedq.s. slowly to the mixer and the mixing continued for an additional 5minutes. The wet granulation is passed through a 20 mesh screen, driedat room temperature for 16 hours and passed again through a 20 meshscreen. Finally, 1.5 wt % of magnesium stearate is added to thegranulation and all the ingredients mixed in a roller mill for 1 to 3minutes.

A second composition is prepared by mixing 64.30 wt % of polyethyleneoxide having a molecular weight of 5,000,000 grams per mole with 29.20wt % sodium chloride and the mix is passed through a 40 mesh screen.Then, the just prepared mixture is mixed with 5.00 wt %hydroxypropylmethylcellulose having a number average molecular weight of9,200 grams per mole and 1.00 wt % ferric oxide for 10 minutes in amixer. Then, anhydrous ethanol q.s. is slowly added to the blendingmixture and all the ingredients mixed for an additional 5 minutes. Thefreshly prepared wet granulation is passed through a 20 mesh screen,allowed to dry at room temperature for 16 hours, and again passedthrough a 20 mesh screen. The screened granulation is mixed with 0.50 wt% of magnesium stearate in a roller mill for 1 minute.

A drug core is prepared by adding 328 mg of the first composition to atablet press and tamped, then 164 mg of the second composition is addedto the press and the two compositions pressed into a two-layered drugcore.

The compressed core is then coated with a subcoat comprisingapproximately 5 mils of 40 wt % cellulose acetate having an acetylcontent of 39.8%, 50 wt % of triacetin, 4 wt % of polyvinyl pyrrolidonewith average molecular weight of 40,000 grams per mole and 6 wt % ofpolyoxyethylene sorbitan tristearate. The subcoat is applied asdescribed in Example 1.

An overcoat composition is prepared by mixing 70 wt % ofhydroxypropylmethylcellulose having a molecular weight of 11,900 gramsper mole with 30 wt % polyethylene glycol having a molecular weight of3350. The overcoat is coated to a thickness of approximately 1 mil andthe two coats annealed as described in Example 1. The final dosage formcomprises 66 mg of drug. A 20 mil orifice is drilled through the twocoats on the drug layer side. The dosage form, in an in vitro fluidenvironment, exhibited a mean release rate of 4.4 mg/hr.

EXAMPLE 3

The procedures set forth above were followed in the present example toprovide the following dosage form: A dosage form comprising a firstcomposition weighing 301 mg and comprising 4.0 wt % prazosinhydrochloride; 90.5 wt % of polyethylene oxide having a molecular weightof 90,000 grams per mole; 5.0 wt % hydroxypropylmethylcellulose having amolecular weight of 11,300 grams per mole; and 0.50 wt % magnesiumstearate; a second composition in layered relation to the firstcomposition, the second composition weighing 200 mg and comprising 64.5wt % coagulated polyethylene oxide having a molecular weight of about5,000,000; 29.0 wt % sodium chloride; 5.0 wt %hydroxypropylmethylcellulose having a molecular weight of 11,300 gramsper mole; 1.0 wt % ferric oxide; and 0.50 wt % magnesium stearate. Thecompressed two-layered core is coated with a subcoat weighing 74.8 mgand comprising 40 wt % cellulose acetate having an acetyl content of39.8%; 54 wt % triacetin and 6.0 wt % polyoxyethylene sorbitantristearate. The overcoat weighs 10.5 mg and comprises 70 wt %hydroxypropylmethylcellulose having a molecular weight of 11,900 gramsper mole, and 30 wt % of polyethylene glycol 3350. The dosage formcomprises a 20 mil passageway on the drug layer side and exhibits a meanrelease rate of 0.74 mg/hr, with a nominal T-90 of 11 hours.

EXAMPLE 4

The procedures set forth above were followed in this example to providea dosage form comprising: a drug core weighing 323.2 mg comprising 5.96wt % salbutamol hemisulfate, 89.04 wt % sodium chloride, 2.0 wt %polyvinylpyrrolidone, 2.0 wt % cross-linked sodiumcarboxymethylcellulose and 1.0 wt % magnesium stearate; a subcoatcomprising 40 wt % cellulose acetate having an acetyl content of 39.8%,54 wt % triacetin and 3 wt % polyoxyethylene sorbitan mono-oleate and 3wt % polyoxyethylene sorbitan monolaurate; and an overcoat comprising 35wt % hydroxypropylmethylcellulose having a molecular weight of 11,900grams per mole, 35 wt % hydroxypropylcellulose having a molecular weightof 73,000 grams per mole, and 30 wt % polyethylene glycol 3350. Thedosage form was annealed as described previously. The dosage form hadtwo 10 mil orifices positioned one on each side, a mean release rate of1.0 mg/hr, and a nominal T-90 of 27 hrs.

EXAMPLE 5

The procedure set forth in Example 1 is followed with all the conditionsas set forth, except that 32 grams of cellulose acetate having an acetylcontent of 32% is mixed with 32 grams of cellulose acetate having anacetyl content of 39.8%, which blend is milled to a particle size of 10microns.

EXAMPLE 6

The procedures described in the above examples were followed in thisexample to provide a delivery device with the following structure: (a)an osmotic core weighing 521 mg and comprising 94 wt % potassiumchloride, 5 wt % polyvinyl pyrrolidone and 1 wt % magnesium stearate;(b) an annealed latex wall, which wall comprises: (i) a subcoat 2.4 milsthick, weighing 31.2 mg and comprising 38.1 wt % cellulose acetatehaving an acetyl content of 39.8%, 54 wt % triacetin, and 6 wt % Tween65 and, (ii) an overcoat 3.4 mils thick, weighing 17.9 mg and comprising70 wt % hydroxyproplymethylcellulose having a molecular weight of 11,900and 30 wt % polyethylene glycol. The device had a 10 mil orifice, acollapse pressure of 104±11 mm Hg, an osmotic water permeability value,k, of 6.3×10⁻⁴ cm mil/atm hr. The device was annealed 1 day at 45° C. ina forced air oven. The rate of release for the device is seen in FIG. 7and the cumulative amount released is seen in FIG. 8.

An embodiment of the invention pertains to a method for administering adrug to the gastrointestinal tract to establish a drug blood level. Themethod comprises the steps of: (A) admitting into the gastrointestinaltract an osmotic dosage comprising: a wall comprising a non-toxiccomposition that is permeable to the passage of fluid and substantiallyimpermeable to the passage of a drug; which wall surrounds and forms:(1) a compartment comprising a gastrointestinal administrable drug; and,(2) at least one exit passageway in the wall connecting the exterior ofthe dosage form with the interior of the dosage form; (B) imbibing fluidthrough the wall into the compartment at a rate determined by thepermeability of the wall and the osmotic pressure gradient across thewall to form in the compartment a dispensable composition that ishydrodynamically and osmotically pumped from the dosage form through thepassageway; (C) thereby delivering the drug in a therapeuticallyeffective amount to the gastrointestinal tract for passing into theblood circulation for establishing a blood level over a prolonged periodof time.

The invention pertains to an osmotic therapeutic system manufacturedwith an annealed wall for delivering a drug at a controlled rate overtime. While there has been described and pointed out the novel featuresof the invention as applied to presently preferred embodiments, thoseskilled in the art will appreciate that various modifications, changesand omissions in the invention illustrated, described and claimed can bemade without departing from the spirit of the invention.

We claim:
 1. An annealed composition for a pharmaceutically acceptabledosage form comprising:(a) a first oil-in-water composition comprising15% to 95% of a member selected from the group consisting of a celluloseether, a cellulose ester and a cellulose ester-ether, 2% to 75% of aplasticizer, and 0.1% to 20% of an emulsifying agent comprising a memberselected from the group consisting of a nonionic, anionic and cationicagent; (b) a second composition comprising a member selected from thegroup consisting of a hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose andmethylcellulose, and optionally a plasticizer, and wherein the firstcomposition and the second composition are annealed at a temperature upto 85° C. for up to 72 hours to yield an annealed composition, andwherein said; (c) annealed composition coats a dosage form selected fromthe group consisting of an osmotic, tablet, capsule, powder, granule,and bead dosage form, which dosage forms comprises; (d) a drugcomprising a physiological and pharmacological therapy effect foradmittance into the gastrointestinal tract of a host in need of therapy.